Combination therapies

Abstract

Provided herein are pharmaceutical compositions comprising a phosphatidylinositol 3-kinase inhibitor, or pharmaceutically acceptable form thereof, in combination with a second agent, or a pharmaceutically acceptable form thereof, wherein the second agent is chosen from one or more of 1) a CDK4/6 inhibitor, 2) an HDAC inhibitor, 3) a MEK inhibitor, 4) a mTOR inhibitor, 5) an AKT inhibitor, 6) a proteasome inhibitor, 7) an immunomodulator, 8) a glucocorticosteroid, 9) a BET inhibitor, 10) an epigenetic inhibitor, 11) a PI3K alpha inhibitor, 12) a topoisomerase inhibitor, or 13) an ERK inhibitor. Also provided herein are methods of treatment comprising administration of the compositions, and uses of the compositions, e.g., for treatment of cancer.

1 - 120 . (canceled) 
     
     
         121 . A method of treating a cancer in a subject in need thereof, comprising administering to the subject a synergistic combination of a PI3K inhibitor, or a pharmaceutically acceptable form thereof, wherein the PI3K inhibitor is (S)-3-(1-((9H-purin-6-yl)amino)ethyl)-8-chloro-2-phenylisoquinolin-1(2H)-one or (S)-2-(1-(9H-purin-6-ylamino)propyl)-5-fluoro-3-phenylquinazolin-4(3H)-one,
 and a second therapeutic agent, or a pharmaceutically acceptable form thereof, wherein the second agent is selected from the group consisting of an HDAC inhibitor, an mTOR inhibitor, a glucocorticosteroid, and a proteasome inhibitor, wherein the combination is synergistic as indicated by a combination index value that is less than 1 for the combination of the PI3K inhibitor and the second therapeutic agent.   
     
     
         122 . The method of  claim 121 , wherein the second therapeutic agent is an mTOR inhibitor. 
     
     
         123 . The method of  claim 122 , wherein the mTOR inhibitor is selected from the group consisting of AP23841, AZD8055, BEZ235, BGT226, deferolimus (AP23573/MK-8669), EM101/LY303511, everolimus (RAD001), EX2044, EX3855, EX7518, GDC0980, INK-128, KU-0063794, NV-128, OSI-027, PF-4691502, rapalogs, rapamycin, ridaforolimus, SAR543, SF1126, temsirolimus (CCI-779), WYE-125132, XL765, zotarolimus (ABT578), torin 1, GSK2126458, AZD2014, GDC-0349, and XL388. 
     
     
         124 . The method of  claim 121 , wherein the second therapeutic agent is a proteasome inhibitor. 
     
     
         125 . The method of  claim 124 , wherein the proteasome inhibitor is selected from the group consisting of bortezomib, carfilzomib, CEP-18770, disulfiram, epigallocatechin-3-gallate, epoxomicin, lactacystin, MG132, MLN9708, ONX 0912, and salinosporamide A. 
     
     
         126 . The method of  claim 124 , wherein the proteasome inhibitor is bortezomib or carfilzomib. 
     
     
         127 . The method of  claim 121 , wherein the second therapeutic agent is an HDAC inhibitor. 
     
     
         128 . The method of  claim 127 , wherein the HDAC inhibitor is selected from the group consisting of vorinostat (SAHA), romidepsin (depsipeptide or FK-228), panobinostat, valproic acid, belinostat (PXD101), mocetinostat, abrexinostat, entinostat, SB939, resminostat, givinostat, CUDC-101, AR-42, CHR-2845, CHR-3996, 4SC-202, CG200745, LAQ824, ACY-1215, and kevetrin. 
     
     
         129 . The method of  claim 127 , wherein the HDAC inhibitor is romidepsin. 
     
     
         130 . The method of  claim 121 , wherein the second therapeutic agent is a glucocorticosteroid. 
     
     
         131 . The method of  claim 130 , wherein the glucocorticosteroid is selected from the group consisting of dexamethasone, aldosterone, beclomethasone, betamethasone, hydrocortisone, cortisone, deoxycorticosterone acetate (DOCA), fludrocortisone acetate, methylprednisolone, prednisolone, and prednisone. 
     
     
         132 . The method of  claim 121 , wherein the method comprises administering the PI3K inhibitor, or pharmaceutically acceptable form thereof, to the subject at an amount of about 0.01 mg to about 75 mg and the second therapeutic agent, or pharmaceutically acceptable form thereof, at an amount of about 0.01 mg to about 1100 mg. 
     
     
         133 . The method of  claim 121 , wherein the cancer is B-cell lymphoma, mantle cell lymphoma, non-Hodgkin's B-cell lymphoma, non-Hodgkin's lymphoma, T-cell lymphoma, cutaneous lymphoma, anaplastic large cell lymphoma, multiple myeloma, follicular lymphoma, or plasmacytoma. 
     
     
         134 . The method of  claim 133 , wherein the cancer is relapsed or refractory. 
     
     
         133 . The method of  claim 133 , wherein the cancer is T-cell lymphoma. 
     
     
         135 . The method of  claim 133 , wherein the cancer is follicular lymphoma. 
     
     
         136 . The method of  claim 121 , wherein the PI3K inhibitor or pharmaceutically acceptable form thereof, and the second therapeutic agent or pharmaceutically acceptable form thereof, are in separate dosage forms. 
     
     
         137 . A method of reducing the likelihood for a subject to develop resistance to a treatment with a PI3K inhibitor, comprising:
 (a) administering to the subject a therapeutically effective amount of a monotherapy comprising the PI3K inhibitor, or a pharmaceutically acceptable form thereof, for a first period of time;   (b) after the first period of time, administering to the subject a therapeutically effective amount of a combination therapy comprising the PI3K inhibitor in combination with an HDAC inhibitor, an mTOR inhibitor, a glucocorticosteroid, or a proteasome inhibitor, for a second period of time; and   (c) optionally repeating steps (a) and (b) one or more times.